Genital infection with oncogenic types of human papillomavirus (HPV) is central to the development of invasive cervical cancer (ICC) and its immediate precursor, cervical intraepithelial neoplasia grades 3 (CIN 3). However, HPV infection is also common in healthy women and usually transient. It is still largely unknown why most of the infections regress spontaneously and what makes HPV infections eventually lead to ICC. We hypothesize that intratypic sequence variations of the virus play an important role in defining consequences of HPV infections. Studies on intratypic variations of HPV types have revealed the presence of a variety of natural variants in all populations examined to date. Given the findings of variable biologic properties of HPV16 and HPV18 variants, we now plan to investigate the etiologic role of intratypic variations of 11 non-HPV16/18 oncogenic types (i.e., HPV31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) that are strongly associated with risk of ICC and CIN 3. None of these 11 types has been carefully studied so far. The proposed study will utilize the existing cervical specimens and epidemiological and clinical data from the population of women who participated in the ASCUS-LSIL Triage Study, the NCI sponsored multi-center clinical trial designed to evaluate strategies for triaging women with equivocal or mildly abnormal Pap smears. We plan to define lineages of the variants for each of 11 HPV types by performing sequence analyses of the partial viral genome and identify nucleotide alterations that are likely to be under selective pressure by population genetic analyses (Aim 1). Our laboratory data will be linked to the ALTS database. By analyzing the linked data file, we will identify a set of the variants that are associated with an increased risk of CIN 3 (Aim 2) and clarify the race-associated distribution and regression of HPV variants (Aim 3). This grant application is in response to the program announcement (PA-07-356). The proposed study will provide important insights into our understanding of HPV variant-related pathogenesis of cervical neoplasia. Knowledge of the intratypic variations of non-HPV16/18 oncogenic types will be of important value to the development of vaccines against these HPV types. Recognition of the etiologic role of HPV variants and the race-associated distribution and persistence of the variants may help with the development of biomarkers to improve screening programs for and clinical management of women with cervical precancerous lesion for a secondary prevention. PUBLIC HEALTH RELEVANCE: Genital infection with oncogenic human papillomavirus (HPV) is central to the development of cervical cancer. HPV types differ biologically and etiologically. The proposed study was designed to investigate the etiologic role of intratypic variations of 11 oncogenic HPV types. Data from the proposed study will be of importance to primary cervical cancer prevention efforts through identification of various natural variants for development of the next generation of vaccines and to secondary prevention efforts through development of biomarkers for improvement of current programs for screening and clinical management.